Guanidine compounds

ABSTRACT

The compounds of this invention are 2,3-unsaturated nitrogen containing heterocyclic compounds with a 3-nitro group and a 2-(2-guanidino-4-thiazolyl alkylamino) group. These compounds have histamine H 2  -antagonist activity. A particular compound of this invention is 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-3-nitro-1,4,-5,6-tetrahydropyridine.

This invention relates to guanidine compounds having histamine H₂-antagonist activity, pharmaceutical compositions containing them andmethods of blocking histamine H₂ -receptors by administering thesecompounds.

Histamine, a physiologically active compound endogenous in mammals,exerts its action by interacting with certain sites called receptors.One type of receptor is known as a histamine H₁ -receptor (Ash andSchild, Brit. J. Pharmac. 1966, 27, 427) and the actions of histaminemediated through these receptors are blocked by drugs commonly called"antihistamines" (histamine H₁ -antagonists) a common example of whichis mepyramine. A second type of histamine receptor is known as the H₂-receptor (Black et al. Nature 1972, 236, 385). These receptors are notblocked by mepyramine but are blocked by burimamide. Compounds whichblock these histamine H₂ -receptors are called histamine H₂-antagonists.

Histamine H₂ -antagonists are useful in treating disease conditionscaused by the biological effects of histamine mediated through H₂-receptors, for example, as inhibitors of gastric acid secretion, in thetreatment of inflammation mediated through histamine H₂ -receptors andas agents which act on the cardiovascular system, for example, asinhibitors of effects of histamine on blood pressure mediated throughhistamine H₂ -receptors.

Cimetidine is an example of a histamine H₂ -antagonist. Cimetidine hasbeen shown to be useful in the treatment of duodenal, gastric, recurrentand stomal ulceration, and reflux oesophagitis and in the management ofpatients who are at high risk from haemorrhage of the uppergastrointestinal tract.

In some physiological conditions the biological actions of histamine aremediated through both histamine H₁ - and H₂ -receptors and blockade ofboth types of receptors is useful. These conditions include inflammationmediated by histamine, for example skin inflammation, and thosehypersensitivity responses due to the action of histamine at H₁ - and H₂-receptors, for example allergies.

A class of guanidine derivatives has now been discovered which areparticularly active as histamine H₂ -antagonists.

Accordingly the present invention provides compounds of formula (I):##STR1## and pharmaceutically acceptable acid addition salts thereof,where Z is sulphur or methylene and A is a covalent bond or methylene orethane-1,2-diyl optionally substituted with one C₁₋₄ alkyl group and asecond C₁₋₄ alkyl group or a phenyl (C₁₋₄ alkyl) group.

It will be appreciated that where A bears two substituents, these willbe selected for stereochemical compatibility.

Examples of C₁₋₄ alkyl groups suitable as substituents on A are methyl,ethyl and n-propyl.

Examples of specific values for A are methylene, ethane-1,2-diyl andpropane-1,2-diyl.

Preferably A is methylene.

Preferably Z is sulphur.

Pharmaceutically acceptable acid addition salts of compounds of formula(I) include for example, those with hydrochloric, hydrobromic,hydroiodic, sulphuric and maleic acids.

The compounds of the invention can be prepared by reacting a compound offormula (II): ##STR2## where Y is either Z(CH₂)₂ NH₂ or, when Z in thecompound of formula (I) is sulphur, a leaving group displaceable bymercaptan, with a compound of formula (III): ##STR3## where X is aleaving group displaceable with an amine when Y is Z(CH₂)₂ NH₂ orHS(CH₂)₂ NH- when Y is a leaving group displaceable by mercaptan; and Ais as defined with reference to formula (I), and optionally thereafterconverting the compound of formula (I) so obtained into a salt.

Examples of leaving groups displaceable by mercaptan are halogen,trisubstituted phosphonium (for example triphenylphosphonium) orsubstituted sulphonyloxy (for example, p-toluenesulphonyloxy,methanesulphonyloxy or trifluoromethanesulphonyloxy).

Examples of leaving groups displaceable by amines are where X is QS-,QSO-, QSO₂ -, or QO- (Q being C₁₋₄ alkyl, aryl or aralkyl). Where X isQO-, Q is preferably phenyl. Preferably the group X is QS- where Q ismethyl.

Where X is a group displaceable with an amine the process is preferablycarried out in the presence of a solvent, for example, a C₁₋₄ alkanol,at elevated temperatures for example the boiling point of the reactionmixture.

Acid addition salts of compounds of formula (I) can conveniently beformed from the corresponding bases by any standard procedure, forexample by reacting the base with an acid in a C₁₋₄ alkanol or by theuse of ion exchange resins to form the required salt. Salts of compoundsof formula (I) can also be interconverted using an ion exchange resin.

The intermediate compounds of formula (III) where X is QS-, QSO-, andQSO₂ - can be prepared by standard methods for example where A ismethylene cyclising a compound of formula (IV): ##STR4## where A and Xare as previously defined and B is chlorine, bromine or iodine; withstrong base.

Preferably B is bromine and preferably the base is sodium hydride. Thereaction can be carried out in an organic solvent or liquid diluent thechoice of which is not critical to the success of the reaction providedthat it is substantially inert to the reagents and product. Suitablesolvents include cyclic ethers for example tetrahydrofuran.

Compounds (IV) where X is QS-, QSO- or QSO₂ - can be prepared in turn byreacting a nitroethylene (V): ##STR5## where Q is as previously definedwith an ω-haloalkylamine (VI):

    NH.sub.2 CH.sub.2 ACH.sub.2 B                              (VI)

where A and B are as previously defined, and thereafter where desiredoxidising the compound of Formula (IV) so obtained. Preferably the amine(VI) is formed in situ from a salt for example a hydrohalide.

Examples of suitable bases are alkali metal alkoxides particularlysodium ethoxide.

Generally the reaction is carried out in a noninterfering solvent forexample a C₁₋₄ alkanol at low temperatures for example 0° C. to roomtemperature.

An intermediate (III) where X is QS-, obtained by this process can beoxidised with one equivalent of hydrogen peroxide, to an intermediate(III) where X is QSO- and to an intermediate (III) where X is QSO₂ - byreaction with two or more equivalents of hydrogen peroxide.

Intermediates of formula (III) where X is QO- can be prepared byreacting a compound of formula (III) where X is QS-, QSO- or QSO₂ - withphenoxide ion. Phenoxide ion can be prepared from phenol and an alkalimetal C₁₋₄ alkoxide for example sodium ethoxide.

The intermediates of formula (III) where X is HS(CH₂)₂ NH can beprepared by reacting a compound of formula (III) where X is QS-, QSO-,QSO₂ or QO- with an amine of formula HS(CH₂)₂ NH₂. The reaction iscarried out in an analogous manner to the reaction between aminecompounds (II) and compounds (III) where X is QS-, QSO-, QSO₂ - or QO-.Preferably X is QS-.

Compounds (VI) are known or can be prepared by analogy with knownprocesses see for example Brown et al. J.A.C.S. 77 1079-92 (1955).

Other processes for preparing intermediates (III) are disclosed in ourco.pending European Patent Application No. 793009721 (publishedApplication No 5984).

The activity of the compounds of formula (I) as histamine H₂-antagonists can be demonstrated by the inhibition ofhistamine-stimulated secretion of gastric acid from the lumen-perfusedstomachs of rats anaesthetised with urethane. This procedure is referredto in Ash and Schild, Brit. J. Pharmac. Chemother., 27, 247 (1966). Thecompound of Example 1 hereafter caused 50% inhibition of maximal acidsecretion at doses of less than 0.1 micromole kh⁻¹ i.v. Their activityas histamine H₂ -antagonists can also be demonstrated by their abilityto inhibit other actions of histamine which, according to the abovementioned paper of Ash and Schild, are not mediated by histamine H₁-receptors. For example, they inhibit the actions of histamine on theisolated guinea pig atrium. The potency of these compounds isillustrated by the effective dose producing 50% inhibition of thehistamine-induced tachycardia in the isolated guinea pig atrium (lessthan 10⁻⁶ Molar for compound of Example 1).

In order to use compounds of formula (I) or a pharmaceuticallyacceptable salt thereof for medical purposes, they are normallyformulated in accordance with standard pharmaceutical practice aspharmaceutical compositions.

The invention further provides pharmaceutical compositions comprising acompound of formula (I) above or a pharmaceutically acceptable acidaddition salt thereof together with a pharmaceutically acceptablecarrier.

Compounds of formula (I) and their pharmaceutically acceptable acidaddition salts may be administered orally, parenterally, cutaneously orrectally.

Compounds of formula (I) and their pharmaceutically acceptable saltswhich are active when given orally can be formulated as syrups, tablets,capsules and lozenges. A syrup formulation will generally consist of asuspension or solution of the compound or salt in a suitable liquidcarrier for example, ethanol, glycerine or water with a flavouring orcolouring agent. Where the composition is in the form of a tablet, anysuitable pharmaceutical carrier routinely used for preparing solidformulations may be used. Examples of such carriers include magnesiumstearate, starch, lactose, sucrose and cellulose.

Typical parenteral compositions consist of a solution or suspension ofthe compound or salt in a sterile aqueous carrier or parenterallyacceptable oil.

Typical compositions for administration to the skin include lotions andcreams in which the compound of formula (I) or salt thereof is containedin a liquid vehicle.

A typical suppository formulation comprises a compound of formula (I) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent suchas gelatin or cocoa butter or other low melting vegetable waxes or fats.

Preferably the composition is in unit dose form such as a tablet orcapsule.

Each dosage unit contains preferably from 15 to 250 mg of a compound offormula (I) or a pharmaceutically acceptable salt thereof calculated asthe free base.

This invention also provides a method of blocking histamine H₂-receptors which comprises administering to an animal an effectiveamount to block said receptors of a compound of formula (I).

The pharmaceutical compositions of the invention will normally beadministered to man for the treatment of peptic ulcers and otherconditions caused or exacerbated by gastric acidity in the same generalmanner as that employed for known histamine H₂ -antagonist, dueallowance being made in terms of dose levels for the potency of thecompound of the present invention relative to known histamine H₂-antagonists. The daily dosage regimen for an adult patient is an oraldose of between 15 mg and 1500 mg and preferably between 20 mg and 250mg or an intravenous, subcutaneous, or intramuscular dose of between 1.5mg and 150 mg, and preferably between 5 mg and 20 mg of compound offormula (I) or pharmaceutically acceptable salt thereof calculated asthe free base, the composition being administered 1 to 6 times per day.

The following Examples illustrate the invention.

EXAMPLES EXAMPLE 12-[2-(2-Guanidino-4-thiazolylmethylthio)ethylamino-]-3-nitro-1,4,5,6-tetrahydropyridine

A solution of 2-(2-guanidino-4-thiazolylmethylthio)ethylamine (0.8 g,3.5 mmol) and 2-methylthio-3-nitro-1,4,5,6-tetrahydropyridine (0.5 g,2.9 mmol) in ethanol (50 ml) was refluxed for 3 hours then left to standat room temperature overnight. The solvent was removed in vacuo and theresidue chromatographed on a silica-gel column. The product was elutedwith ethyl acetate/propan-2-ol (8:2) and recrystallised twice frommethanol/ether. Yield: 0.16 g, 15%. M.P. 211°-212.5° C.

EXAMPLE 22-[2-(2-Guanidino-4-thiazolylmethylthio)ethylamino-]-5,5-dimethyl-3-nitro-1,4,5,6-tetrahydropyridine

The title compound is prepared from2-(2-guanidino-4-thiazolylmethylthio)ethylamine and2-methylthio-3-nitro-5,5-dimethyl-1,4,5,6-tetrahydropyridine by aprocess analogous to that of Example 1.

EXAMPLE 32-[2-(2-Guanidino-4-thiazolylmethylthio)ethylamino-]-3-nitro-5-(2-phenylethyl)-1,4,5,6-tetrahydropyridine

The title compound is prepared from2-(2-guanidino-4-thiazolylmethylthio)ethylamine and2-methylthio-3-nitro-5-(2-phenylethyl)-1,4,5,6-tetrahydropyridine by aprocess analogous to that given in Example 1.

EXAMPLE 4 Preparation of pharmaceutical composition for oraladministration

A pharmaceutical composition is prepared containing:

    ______________________________________                                                              % w/w                                                   ______________________________________                                              The product of Example 1                                                                            55                                                A     Dibasic calcium phosphate dihydrate                                                                 20                                                      Approved colouring agent                                                                            0.5                                                     Polyvinylpyrrolidone  4.0                                                     Microcrystalline cellulose                                                                          8.0                                               B     Maize starch          8.0                                                     Sodium starch glycollate                                                                            4.0                                                     Magnesium stearate    0.5                                               ______________________________________                                    

by mixing together the ingredients A (substituting lactose ormicrocrystalline cellulose for dibasic calcium phosphate dihydrate ifdesired), adding a concentrated solution of polyvinylpyrrolidone, andgranulating, drying and screening the dried granules; adding theingredients B to the dried granules and compressing the mixture intotablets, containing an amount of product corresponding to 100 mg, 150 mgor 200 mg of the free base.

EXAMPLE 5 Preparation of pharmaceutical composition for topicaladministration

A pharmaceutical composition is prepared containing:

    ______________________________________                                                            % w/w                                                     ______________________________________                                            The product of Example 1                                                      Stearyl alcohol       15.0                                                A   Beeswax               8.0                                                     Sorbitan monooleate   1.25                                                    Polyoxyethylene sorbitan monooleate                                                                 3.75                                                    The product of Example 1                                                                            1.0                                                     Sorbitol solution B.P.                                                                              7.5                                                     Citric acid           0.2                                                 B   Sodium citrate        0.05                                                    Methylparaben         0.18                                                    Propylparaben         0.02                                                    Water       100                                                           ______________________________________                                    

A mixture of the ingredients A is heated to 72° and added with stirringto a mixture of the ingredients B at 70°, and the stirring is continueduntil a cream is formed.

We claim:
 1. A compound of formula (I): ##STR6## or a pharmaceutically acceptable acid addition salt thereof, where Z is sulphur or methylene and A is a covalent bond or methylene or ethane-1,2-diyl optionally substituted with one C₁₋₄ alkyl group and a second C₁₋₄ alkyl group or a phenyl (C₁₋₄) alkyl group.
 2. A compound according to claim 1 where A is methylene, ethane-1,2-diyl or propane-1,2-diyl.
 3. A compound according to claim 2 where A is methylene.
 4. A compound according to claim 1 where Z is sulphur.
 5. The compound of claim 1 which is 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino-]-3-nitro-1,4,5,6-tetrahydropyridine.
 6. The compound of claim 1 which is 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino-]-5,5-dimethyl-3-nitro-1,4,5,6-tetrahydropyridine.
 7. The compound of claim 1 which is 2-[2-(2-guanidino-4-thiazolylmethylthio)ethylamino]-3-nitro-5(2-phenylethyl)-1,4,5,6-tetrahydropyridine.
 8. A pharmaceutical composition having histamine H₂ -receptor blocking activity comprising in an amount effective to block said receptors a compound of claim 1 and a pharmaceutically acceptable carrier.
 9. A method of blocking histamine H₂ -receptors which comprises administering to an animal an effective amount to block said receptors of a compound of claim
 1. 